This project is focused on understanding mechanisms underlying sex differences in psychopathology. We will study effects of sex-differential prenatal androgen exposure on brain and behavioral systems of positive and negative valence. Our long-term goal is to understand how sex-related risk for mental illness develops from the interplay of physical sexual differentiation and socialization processes. In this initial step, our objective is to determine how prenatal androgens contribute to the development of circuits that show sex differences and that are responsible for functional domains important for mental health. Prenatal androgens are hypothesized to contribute to neural substrates of reward (positive valence) and emotional memory (negative valence). This hypothesis will be tested in a neuroimaging study in congenital adrenal hyperplasia (CAH), a genetic disorder causing high androgen levels during prenatal development. We will compare 20 women and 20 men with CAH to their same-sex unaffected siblings on magnetic resonance imaging (MRI), behavioral, and self-report measures of reward and emotional memory. Both sexes are affected by CAH, but females show more behavioral effects than males because their androgen levels are more sex-atypical; females thus provide an excellent opportunity for hypothesis-testing of androgen effects, whereas males provide control for non- androgen influences related to CAH, and enable exploration about timing and dose of androgen effects. We expect that aspects of brain structure and function that differ between sexes will differ in women with vs. without CAH, and we study this using sex-differentiated measures of reward and emotional memory systems and functional connections to prefrontal cortex (PFC), and brain structure. Compared to unaffected sisters, women with CAH should have (a) faster response to cues signaling high monetary rewards, and increased striatal activity and decreased striatum-PFC connectivity during reward presentation, (b) reduced memory for threat/fear stimuli, and altered lateralized amygdala activity and reduced amygdala-PFC connectivity during encoding of accurately-recalled stimuli, and (c) increased volume in regions larger in men (amygdala, hypothalamus), and reduced volume in regions larger in women (hippocampus, proportion of gray matter). The outcome will be to identify the importance of prenatal life as a sensitive period for sex differences in psychiatric disorders, by showing how prenatal androgens influence circuits responsible for two sex-related domains linked to sex-related disorders. CAH provides a valuable rare model to determine the importance of early sensitive periods that cannot easily be accomplished in typical samples, and thus a unique opportunity to examine mechanisms underlying sex-related psychopathology. Future work will focus on identifying how hormonally-influenced neural systems are modified by pubertal hormones and gendered social environments.